The immune checkpoint inhibitor pembrolizumab appeared well-tolerated with encouraging antitumor activity as treatment of patients with non-muscle invasive bladder cancer who are unresponsive to Bacillus Calmette-Guerin, according to the updated follow-up from the phase 2 KEYNOTE-057 clinical trial.
The immune checkpoint inhibitor pembrolizumab (Keytruda) appeared well-tolerated with encouraging antitumor activity as treatment of patients with non-muscle invasive bladder cancer (NMIBC) who are unresponsive to Bacillus Calmette-Guérin (BCG), according to the updated follow-up from the phase 2 KEYNOTE-057 clinical trial (NCT02625961) presented during the 35th European Association of Urology Virtual Annual Congress.
Pembrolizumab was generally well-tolerated as treatment of this patient population, with no new risks identified. Patients were also able to maintain their health-related quality of life. The rates of pathological upstaging to muscle-invasive disease were also low in patients who underwent radical cystectomy after discontinuation of the study treatment.
Overall, 93 patients were evaluable for efficacy and 102 patients for safety. Three patients had completed treatment, but treatment was ongoing in 7 patients. A total of 86 patients discontinued treatment due to persistent disease in 38 patients and recurrent disease or disease progression in 33 patients.
The median time from enrollment to database cutoff was 28.4 months (range, 18.2-40.5), and there was no progression of muscle-invasive or metastatic bladder cancer at the time of treatment discontinuation, according to study-specified disease assessments.
The complete response (CR) rate was 40.6% (95% CI, 30.7-57.1). The duration of response lasted for more than 1 year in 18 of the 39 patients who responded. In the 58 patients who did not have a CR, 40 (41.7%) had persistent disease, 6 (6.3%) had recurrent disease, 9 (9.4%) had NMIBC stage progression, and 1 (1.0%) had a non-bladder malignancy. One patient was not evaluable.
The median duration of CR was 16.2 months (range, 0+ to 26.8+), and 57.4% of patients maintained their CR for at least 12 months. In addition, 45.2% of patients maintained their CR at the last follow-up. Recurrent disease after a CR occurred in 47.6% of patients.
The median overall survival (OS) was not reached, but the 12-month OS rate was 98.0%.
Most patients, including 71.1% for FACT-G total and 77.7% for FACT-G physical well-being subscales, had improved or stable scores from baseline. In FACT-G and FACT-G physical well-being subscales, the increases in scores were ≥7 and ≥3-point, and changes occurred between −7 and +7 or −3 and +3 points, respectively.
Ten of the 23 responders (43.5%) and 28 of the 60 of the non-responders (46.7%) underwent a radical cystectomy after treatment discontinuation.
Treatment-related adverse events (TRAEs) of any grade occurred in 67 patients (55.7%). Grade 3/4 TRAEs were observed in 13 patients (12.7%), which included hyponatremia (2.9%), arthralgia (2.0%), adrenal insufficiency, adrenocorticotropic hormone deficiency, cholestatic hepatitis, dermatitis, hypophosphatemia, lymphocyte count decrease, malaise, pulmonary embolism, pruritis, syncope, and type 1 diabetes mellitus (1.0%, each).
The most common TRAEs of any grade that occurred in 10% or more of patients were diarrhea, fatigue, and pruritus.
At the time of radical cystectomy among the patients who discontinued treatment, 36 patients underwent pathological staging. NMIBC was observed in 3 patients
Thirty-six patients who discontinued treatment received a radical cystectomy, and 6 of the 36 patients did not have pathological upstaging. Three patients had NMIBC of stage pTa, 18 of stage pTis, and 6 of stage pT1. The median interval between the last dose of pembrolizumab and radical cystectomy among the patients without pathological upstaging was 134.5 days (range, 60-149) and 77 days (range, 42-448) in the patients with NMIBC. Three patients had MIBC (including 2 patients with pT2 stage and 1 with pT3 stage).
“With additional follow-up, the KEYNOTE-057 study continues to show clinically meaningful antitumor activity of pembrolizumab in BCG-unresponsive carcinoma in situ of the bladder with or without papillary tumors and are ineligible or elected not to undergo radical cystectomy,” lead author Joost L. Boormans, PhD, of the Aramus Medical Center, in Rotterdam, Netherlands, said during his presentation.
The single-arm study evaluated both the safety and efficacy of pembrolizumab in patients with high-risk NMIBC who were unresponsive to BCG.
Cohort A included patients with BCG-unresponsive carcinoma in situ of the bladder with or without papillary tumors and were ineligible for radical cystectomy. These patients were treated with the immune checkpoint inhibitor at 200 mg every 3 weeks, and treatment continued for 2 years if there was no recurrence or progression at any assessment. The primary end point was CR rate, while the secondary end point was duration of response.
Boormans JL, De Wit R, Kulkarni GS, et al. Updated Follow-Up From KEYNOTE-057: Phase 2 Study of Pembrolizumab (pembro) for patients (pts) with High-Risk (HR) Non–Muscle Invasive Bladder Cancer (NMIBC) Unresponsive to Bacillus Calmette-Guérin (BCG). Presented at: 35th Annual European Association of Urology Congress; July 20-26, 2020; Virtual. Poster 772.